CDRH Scientific Perspective on Chemical Analysis and Toxicological Risk Assessment for Medical Devices Presenters: Berk Oktem, Alan Hood, Jennifer Goode Co-authors: Eric Sussman, Samanthi Wickramasekara SOT-MDCPSS Webinar, May 22, 2019
Disclaimer The findings and conclusions in this presentation have not been formally disseminated by the Food and Drug Administration, are the views of the authors, and should not be construed to represent any agency determination or policy. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by Department of Health and Human Services. www.fda.gov 2 SOT-MDCPSS Webinar, May 22, 2019
Objective Discuss common analytical chemistry and toxicological risk assessment issues related to the 2016 CDRH Biocompatibility Guidance, ISO 10993-18 and ISO 10993-17. www.fda.gov 3 SOT-MDCPSS Webinar, May 22, 2019
Outline 1. Introduction: 21 st Century Cures Act of 2016, least burdensome approaches 2. Background: Why Chemical Analysis and Toxicological Risk Assessment 3. Part I: Chemical Analysis Approaches 4. Part II: Toxicological Risk Assessment www.fda.gov 4 SOT-MDCPSS Webinar, May 22, 2019
Introduction 21 st Century Cures Act - Section 3058: Least Burdensome Device Review • CDRH Guidance :”The Least Burdensome Provisions: Concept and Principles” February 2019. – We define “least burdensome” to be the minimum amount of information necessary to adequately address a relevant regulatory question or issue through the most efficient manner at the right time – The least burdensome provisions do not change the standards (i.e. level of information needed) for premarket approval or substantial equivalence – Least burdensome provisions form a ‘two way street’: “Industry should not submit information unrelated to the regulatory decision to FDA.” https://www.fda.gov/media/73188/download www.fda.gov 5 SOT-MDCPSS Webinar, May 22, 2019
Background: Why Chemical Analysis and Toxicological Risk Assessment 2016 CDRH Biocompatibility Guidance – “potential risks from a biocompatibility perspective should be identified ” – “what information is already available regarding those risks and identify the knowledge gaps that remain” – “ address the knowledge gaps either by biocompatibility testing or other evaluations that appropriately address the risks” https://www.fda.gov/media/85865/download www.fda.gov 6 SOT-MDCPSS Webinar, May 22, 2019
Background: Why Chemical Analysis and Toxicological Risk Assessment 2016 CDRH Biocompatibility Guidance – “Inherent in the review of medical devices is an understanding of the body’s entire exposure to the medical device, including all chemical entities contained within the device. ” – “ chemical analyses can be used to assess the toxicological risk of the chemicals that elute from devices. For example, chemical analysis using exhaustive extraction techniques (per ISO 10993-12) can also be helpful to evaluate long- term toxicity endpoints such as potential carcinogens…In addition, the outcomes of chemical analyses are often sensitive to the parameters of the test. Extraction solvents should be selected to optimize compatibility with the device materials ” https://www.fda.gov/media/85865/download www.fda.gov 7 SOT-MDCPSS Webinar, May 22, 2019
Background: Applicability of Other Industry Approaches • Devices are not drugs • Devices are not pharmaceutical packaging • Devices are not food containers • Analytical approaches that generate data adequate for toxicological risk assessment can be useful for medical devices Material characterization of medical devices require unique approaches www.fda.gov 8 SOT-MDCPSS Webinar, May 22, 2019
Background: Brief Comparison of Different Industries Drug Products Medical Devices Contact Until expiration date 1 minute to lifetime Dose Single, multiple or repeated Single, multiple or repeated, continuously Impurities Leachables delivered with the Extractables released from identification drug product (tablet, the device components that liquid/solution) contacts the body indirectly or directly. www.fda.gov 9 SOT-MDCPSS Webinar, May 22, 2019
Part I: Chemical Analysis Approaches – Expanded Information in ISO FDIS 10993-18:2019 – Chemical Analysis: Purpose-Contact and other Considerations – Considerations for Planning an Extraction Study and Analytical Tools – Identification of Non-targeted Extractables – Quantification and Reporting www.fda.gov 10 SOT-MDCPSS Webinar, May 22, 2019
Part I: Chemical Analysis Approaches Non-targeted screening : • Extraction: exhaustive or exaggerated extraction • Data generation: multiple analytical methods • Detect, identify and quantify: To provide data to support toxicological risk assessment www.fda.gov 11 SOT-MDCPSS Webinar, May 22, 2019
What Standards Are Used? - A standardized method for complete chemical analysis of medical device materials does not currently exist. - CDRH partially recognizes ANSI AAMI BE83:2006/(R)2011 (there are differences between ISO 10993-18: 2005 and BE83) - CDRH does not recognize PQRI recommendations (2006) - The "ISO FDIS 10993-18:2019 (recently balloted) includes additional details on analytical instruments, quantification methods, etc." https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/search.cfm www.fda.gov 12 SOT-MDCPSS Webinar, May 22, 2019
Expanded Information in ISO FDIS 10993-18:2019 Concepts that do not appear in ISO 10993-18:2005 – AET: Analytical Evaluation Threshold, a pre-determined concentration above which an extractable is expected to be identified and semi-quantified.(definitions) – The importance of identification (not new as concept but….) – Expansion of reporting requirements ….and more www.fda.gov 13 SOT-MDCPSS Webinar, May 22, 2019
Analytical Evaluation Threshold: Reporting and Identification Limit AET ( μg /ml) = DBT ( μg /day) x (A/(BxCxD)) ÷ UF Dose-Based Threshold (DBT) = Threshold of Toxicological Concern (ICH M7) A = number of medical devices extracted B = extract volume C = number of medical devices that contact the body D** = dilution factor (D>1), if concentrated (D<1). If not diluted (D=1) UF = uncertainty factor of analytical methods (UF >=1) **D is optional: extract processing should be accounted for. ISO FDIS 10993-18: 2019, Annex E www.fda.gov 14 SOT-MDCPSS Webinar, May 22, 2019
Analytical Evaluation Threshold: Reporting and Identification Limit Device Contact Duration DBT (µg/day) Limited and prolonged (<30 days) 120 Permanent/Long-term (>30 days) 1.5 Dose-Based Threshold (DBT) = Threshold of Toxicological Concern (ICH M7) AET > LOQ , LOD www.fda.gov 15 SOT-MDCPSS Webinar, May 22, 2019
Chemical Analysis Considerations Common Questions: • Purpose: what biocompatibility endpoints are addressed? • Device Information • Test Article Information • Extraction • Analysis • Identification • Quantification Note: Chemical equivalency involves different considerations and will not be discussed today. www.fda.gov 16 SOT-MDCPSS Webinar, May 22, 2019
Purpose, Device and Test Article Information Considerations • Purpose: to support biocompatibility evaluation of some biological endpoints (e.g., Acute Systemic Toxicity, Subacute/Subchronic Toxicity, Chronic Toxicity, Genotoxicity, Carcinogenicity) • Device information: material list (direct and indirect contact) • Test article information: final finished device, manufacturing considerations • Information gathering: determine the scope of any analytical testing • Extraction design: rationale for solvent selection, time/temperature of extraction, etc. www.fda.gov 17 SOT-MDCPSS Webinar, May 22, 2019
Analysis Considerations Duration of Contact Limited Prolonged Long-Term/ Permanent (<24 h) (1-30 days) (>30 days) Exaggerated extractions Exhaustive extractions Duration/ Number or worst case clinically or worst case clinically Exhaustive extractions of Cycles relevant conditions relevant conditions Polar and non-polar Polar and non-polar solvents Polar, mid-polar and Number of solvents solvents (or polar and (or polar and mid-polar if non-polar mid-polar if justified) justified) NVR analysis to NVR analysis to NVR Analysis NVR analysis may be support if exhaustion is support if exhaustion is Performed? considered achieved achieved www.fda.gov 18 SOT-MDCPSS Webinar, May 22, 2019
System Suitability/Qualification Establishing instrument sensitivity • Following practices for robust method – 5 Point Calibration Curve – Use of internal standards – Use of more reference standards with varying response factors • Selecting reference standards: Use of reference standards that match the expected/observed extractables can improve identification and quantification – Example: • Polyvinyl chloride (PVC): DEHP • Polyurethane: 4,4’ -MDI www.fda.gov 19 SOT-MDCPSS Webinar, May 22, 2019
Considerations for Planning an Extraction Study and Analytical Tools • Non-targeted vs. targeted methods • Non-targeted (screening): detect, identify and semi-quantify extractables above AET • Targeted: specific purpose (e.g. formaldehyde) – Could include specialized methods (e.g. 2,4 DNPH derivatization for carbonyl compounds) www.fda.gov 20 SOT-MDCPSS Webinar, May 22, 2019
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